Nitric oxide (NO) is a potent mediator of many biological functions, for example acting as a vasodilator, neurotransmitter, and inflammatory mediator at nanomolar to micromolar concentration. It inhibits platelet activation, and has been shown to modulate endothelial/leukocyte adhesion. As a component of the immune system, nitric oxide has been shown to modulate the activity and metabolism of macrophages and neutrophils. See, e.g., M. Freelisch, J. Cardiovascular Pharmacology, 17 (Suppl. 3), S25-S33 (1991).
Nitric oxide is a nonpolar, lipophilic molecule capable of freely and rapidly permeating cell membranes. Nitric oxide is unstable at physiological O.sub.2 tensions. It is generally not administered for therapeutic purposes systemically via the circulation because it is rapidly inactivated (in seconds) by oxyhemoglobin within red blood cells. This has primarily limited the therapeutic application of free nitric oxide to delivery to the lungs locally by inhalation, where it acts as a vasodilating agent to improve lung ventilation.
As a result of the instability and inconvenient handling of aqueous solutions of nitric oxide, there is increasing interest in utilizing compounds capable of generating nitric oxide in situ. Nitric oxide "prodrugs" (typically referred to as nitric oxide donors, see M. Freelisch, Eur. Heart J., 14, 123-132 (1996)) exert their pharmacological actions after they have been metabolized into nitric oxide. For example, thrombogenesis and vasoconstriction of the arteries, which have limited the use of implantable chemical sensors, have been alleviated by incorporating a nitric oxide-releasing compound, an N,N-dimethylhexanediamine nitric oxide (DMHD/N.sub.2 O.sub.2) adduct, into the sensor (C. Espadas-Torre et al., J. Am. Chem. Soc., 119, 2321-2322 (1997)). Likewise, complications such as thrombi and emboli that arise from cardiopulmonary bypass surgery and other major surgical interventions are treatable with nitric oxide donors (M. K. Dewanjee, ASAIO J., 43, 151-159, (1997)).
Current methods for nitric oxide delivery using nitric oxide donors suffer from numerous drawbacks. Systemic delivery to achieve a local effect such as prevention of thrombosis in an extracorporeal circuit requires a very large dose to compensate for dilution by the blood, and careful monitoring for systemic effects such as hypotension. With local delivery, a trade-off must be made between the biological effectiveness and the duration of action. The half life (or time for one half of the donor compound to decompose to yield nitric oxide) of different nitric oxide donors can vary from a few seconds to a week or more under physiological conditions. A short half-life donor will yield a high local concentration of free nitric oxide. However, the duration for delivery will be limited, especially if the donor drug is not stable within the device itself. Conversely, local delivery of long half life donors allows a longer duration of treatment at the expense of lower local concentration of free nitric oxide. Other limitations are particular to selected nitric oxide donors, such as the requirement for biological conversion (e.g., organic nitrates), toxic byproduct formation (e.g., sodium nitroprusside) or incompatibility with various sterilization methods (e.g., decomposition inactivation upon exposure to heat, steam, or gamma sterilization).
What is needed is a biologically compatible material capable of substantially continuous delivery of free nitric oxide at an intended site, preferably in a substantially uniform manner.